Precision Medicine Approach to Prostate Cancer Active Surveillance Project Summary: Prostate cancer (PCa) accounts for over 28,000 deaths per year and was the second-greatest cause of cancer death among men in 2012. There will be over 241,000 new diagnoses of PCa this year with the majority opting for primary curative therapies, such as radiation or surgery, with associated potential side effects and subsequent declines in health related quality of life. Widespread use of prostate-specific antigen (PSA)-screening has led to profound stage migration, with the majority of newly diagnosed cases being clinically localized and of low grade. Such stage migration has resulted in the number of diagnoses far outnumbering the number of lethal cases, i.e. over diagnosis of those cancers that would never progress or cause harm to the patient if left untreated. Estimates of the proportion of over diagnosed PCa range from 15-84%, depending on the definition of occult or latent disease. PSA screening practices have changed minimally after publication of large PSA screening trials, and it is expected that even after the recent United States Preventive Services Task Force (USPSTF) recommendations, patients will continue to drive PCa screening, and other guidelines still promote informed decision-making. Given the often indolent course of screen-detected PCa, active surveillance (AS) - or careful monitoring of the cancer, most often with PSA kinetics and serial biopsy, with selected intervention based on these parameters - is an emerging initial management alternative for PCa that appears unlikely to threaten quality or length of life. AS is a management strategy for those with low-grade, low volume malignancy, who are followed carefully and treated with curative intent based on apparent progression. However, most AS strategies call for serial biopsies to determine whether there is disease progression, and these biopsies have potential complications such as infection. Supplementing AS with reliable biomarkers to predict disease progression would greatly enhance the appeal of this approach. We hypothesize that biomarkers of disease aggressiveness and prognosis can be interrogated in early stage PCa and that these biomarkers will reliably predict PCa progression and/or under-staging and grading. We aim to elucidate this challenge in this proposal. We will confirm a novel panel of tissue-based biomarkers to determine the presence of or progression to aggressive disease. This novel, biopsy-based multi-gene quantitative RT-PCR assay developed by Genomic Health, Oncotype DX Prostate Cancer Assay, discriminates aggressive from indolent cancer on multivariate modeling of prostate cancer patients. We will accomplish this using the PASS cohort (n=1000 men), the largest, prospective, multi- site AS study in North America. We will also evaluate emerging tissue-based biomarkers for aggressive PCa in men on AS using Next Generation DNA sequencing and will also assess on biopsy samples TMPRSS2:ERG and PTEN status and determine associations with aggressive PCa.